DETAILED ACTION
Notice of Pre-AIA or AIA Status
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Continued Examination Under 37 CFR 1.114
2. A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on Oct. 10, 2025 has been entered.
Claim Amendments
3. The amendments filed Oct. 10, 2025 have been entered. Claims 1-129, 139-143, and 145-153 was cancelled. Claims 130,133, and 138 have been amended.
Claims 130-138, 144 and 154-155 are under consideration in this Office Action.
Withdrawn Claim Objections and Rejections
4. The objection of claims 130, 133 and 138 is withdrawn in view of Applicants amendments.
5. The rejection of claim 138 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, is withdrawn in view of Applicants amendments.
Maintained Grounds of Rejection
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
6. Claims 130-136 and 154-155 are rejected under 35 U.S.C. 103 as being unpatentable over Ella et al., (WO 2020095324 published May 2020; priority to Nov 10, 2018) in view of Konadu et al. (Infect Immun. 2000 Mar; 68(3): 1529–1534).
The claims are drawn to an immunogenic composition comprising: a) a Salmonella enterica serovar typhi Vi polysaccharide-tetanus toxoid (TT) conjugate antigen; and b) a Salmonella enterica serovar paratyphi A O-specific polysaccharide (OSP) diphtheria toxoid (DT) conjugate antigen.
Ella et al., teach multivalent conjugate compositions against Salmonella diseases along with combined vaccine composition of glycol-conjugates in bivalent combinations [abstract]. The immunogenic composition comprise two or more of an antigen of Salmonella enteritidis, an antigen of Salmonella typhimurium, an antigen of Salmonella typhi; and/or an antigen of Salmonella paratyphi, wherein each antigen is conjugated to one or more carrier molecules. The typhoid Vi polysaccharide is covalently conjugated on the carrier protein to form conjugative vaccine that can be used to generate active immunity in humans and other mammals, and for preventing typhoid infection. After the typhoid Vi polysaccharide is conjugated with protein, the recognition mode of organism to typhoid Vi antigen is changed into T cell depended antigen that can be used for immunity of all people and possesses obvious effect for boosting immunity [para 12]. Ella et al., teach stable conjugate vaccine formulations for protections against Salmonella typhii, and methods of conjugation between Vi-polysaccharide of S. typhii to tetanus toxoid as the carrier protein, responsible for producing improved T-dependent immune response against Typhoid fever caused by Salmonella typhi [para 15]. The immunogenic composition, wherein the one or more carrier molecules comprises one or more of tetanus toxin, tetanus toxin heavy chain proteins, diphtheria toxoid, tetanus toxoid, Escherichia coli heat-labile toxin B subunit, Neisseria meningitidis outer membrane complex, and modifications thereof [para 27]. Thus teaching claim 144. One embodiment of the invention comprises S. typhi Vi conjugated by carbodiimide mediated modification of S. typhi Vi polysaccharide with adipic acid dihydrazide (ADH) that introduces reactive hydrazide groups that are then used to link to tetanus toxoid (TT) via a second carbodiimide step [para 81]. Thus teaching claim 130 in part. Table 1 teach a bivalent vaccine composition comprising a bivalent conjugate vaccine containing Salmonella typhi Vi conjugate and Salmonella paratyphi A conjugate (Single dose) 5-30ug each/dose, PBS with tween 80.
The immunogenic composition comprises a pharmaceutically acceptable buffer such as PBS and Tween 80 [para 28]. It is noted that Tween 80 is also generically known as polysorbate 80, thereby teaching claim 136. The immunogenic composition comprises a stabilizer such as 2-phenoxy ethanol [para 29]. Thus teaching claim 131. The immunogenic composition comprises an adjuvant [para 30]. Adjuvants include, but are not limited to analgesic adjuvants, inorganic compounds such as alum, aluminum hydroxide, aluminum phosphate and others [para 72]. Thus teaching claim 132. Each antigenic conjugate is present in the immunogenic composition at a dose range of about 5 μg/dose to about 30 μg/dose [para 31]. Thus teaching claim 133. Stabilizing agents include, for example, pharmaceutically acceptable sugars [para 71]. The trivalent Salmonella conjugate vaccine drug product in multi-dose vials and the bivalent Salmonella conjugate vaccine drug product in both multi-dose and mono-dose vials were maintained in controlled storage at 2-8° C. with stability being monitored only for the Vi conjugate component [para 118]. Real-time stability testing was carried for evaluating the stability of vaccine compositions according to embodiments of the invention at recommended storage conditions of 2-8° C [See example 7]. Thus, compositions according to embodiments of the invention were found to be stable at recommended storage conditions of 2-8° C [para 157]. It is noted that neither claim 154 nor 155 include any additional components. Thus Ella et al., teach claims 154-155.
Therefore, Ella et al., clearly teach an immunogenic composition comprising a Salmonella enterica serovar paratyphi A conjugate antigen and Salmonella enterica serovar typhi Vi polysaccharide-tetanus toxoid (TT) conjugate antigen to treat typhoid fever; but does not teach the conjugate of Salmonella enterica serovar paratyphi A with O-specific polysaccharide (OSP) and diphtheria toxoid (DT).
Konadu et al., teaching Salmonella enterica serovar paratyphi A O-specific polysaccharide (O-SP) was activated with 1-cyano-4-dimethylaminopyridinium tetrafluoroborate (CDAP) and bound to tetanus toxoid (TT) with adipic acid dihydrazide as a linker (SPA-TT(1)) or directly (SPA-TT(2)) where a significant rise in the IgG anti-LPS titer was elicited by the first injection. Therefore Konadu et al., disclose an immunogenic composition comprising Salmonella enterica serovar paratyphi A OSP saccharide- tetanus carrier protein conjugate just as instantly claimed in claims 130 and 134. Both S. enterica serovars Typhi and Paratyphi are inhabitants and pathogens of humans only [page 1529, col. 1]. The clinical results with Vi capsular polysaccharide of S. enterica serovar Typhi were the basis for our prediction that a critical level of serum immunoglobulin G (IgG) to the O-specific polysaccharide (O-SP) will confer protection against S. enterica serovar Paratyphi A [page 1529, col. 1-2]. Vaccination with the surface polysaccharide of S. enterica serovar Typhi (Vi) prevents typhoid fever (65). The immune moiety elicited by Vi is mainly serum IgG antibody (51). The O-SP of S. enterica serovar Paratyphi A alone is not immunogenic (hapten) due to its comparatively low molecular weight [page 1531, col. 2]. S. enterica serovar Paratyphi A O-specific polysaccharide–TT conjugates were safe and elicited IgG antibodies with bactericidal activity in the serum of adults, teenagers, and 2- to 4-year-old children. There is sufficient information about Vi, with S. enterica serovar Typhimurium O-SP conjugates in mice and clinical studies with Shigella O-SP conjugates, to evaluate S. enterica serovar Paratyphi A conjugates for efficacy [page 1532, col. 2]. Representative sera from all groups had bactericidal activity that could be adsorbed by S. enterica serovar Paratyphi A LPS [abstract].
Therefore, it would have been prima facie obvious at the time of applicants’ invention to apply Konadu et al., Salmonella enterica serovar paratyphi A O-specific polysaccharide (O-SP) conjugated to tetanus toxoid to Ella’s immunogenic composition comprising a Salmonella enterica serovar paratyphi A conjugate antigen and Salmonella enterica serovar typhi Vi polysaccharide conjugate antigen in order to treat typhoid fever. One of ordinary skill in the art would have a reasonable expectation of success by incorporating Konadu et al., conjugate because it elicits a significant rise in the IgG anti-LPS titer upon injection. Furthermore, no more than routine skill would have been required to incorporate the conjugate antigen when Ella et al., already teach a bivalent immunogenic composition comprising a conjugate vaccine containing Salmonella typhi Vi tetanus conjugate and Salmonella paratyphi A conjugate. Finally it would have been prima facie obvious to combine the invention of Ella et al., and Konadu et al., to advantageously achieve an immunogenic composition against pathogenic S. enterica serovars Typhi and Paratyphi known to cause typhoid infections/fevers.
Additionally, KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007), discloses combining prior art elements according to known methods to yield predictable results, thus the combination is obvious unless its application is beyond that person's skill. KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007) also discloses that "The combination of familiar element according to known methods is likely to be obvious when it does no more than yield predictable results". It is well known to take an immunogenic composition, where there is no change in the respective function of the conjugates, thus the combination would have yielded a reasonable expectation of success along with predictable results to one of ordinary skill in the art at the time of the invention. Therefore, it would have been obvious to a person of ordinary skill in the art to combine prior art elements according to known methods that is ready for improvement to yield predictable results. The claimed invention is prima facie obvious in view of the teachings of the prior art, absent any convincing evidence to the contrary.
Claim Rejections - 35 USC § 103
7. Claims 137-138 are rejected under 35 U.S.C. 103 as being unpatentable over Ella et al., (WO 2020095324 published May 2020; priority to Nov 10, 2018) in view of Konadu et al. (Infect Immun. 2000 Mar; 68(3): 1529–1534) as applied to claims 130-136, 144 and 154-155 above, and further in view of Levine et al., (US 20130129776 published May 2013 priority to Nov 2011).
Ella et al., in view of Konadu et al., teach an immunogenic composition comprising: a) a Salmonella enterica serovar typhi Vi polysaccharide-tetanus toxoid (TT) conjugate antigen; and b) a Salmonella enterica serovar paratyphi A O-specific polysaccharide (OSP) diphtheria toxoid (DT) conjugate antigen. However, neither specifically teach the inclusion of sucrose, sodium chloride and water as part of the composition.
Levine et al., teach multivalent Salmonella enterica serovar conjugate vaccines comprising conjugates including but not limited to S. Typhi, S. Paratyphi A wherein the conjugates comprise a hapten antigen and a carrier antigen, wherein at least one of the hapten antigens or carrier antigens is characteristic of the Salmonella enterica serovar. Such conjugate vaccines can be in admixture with a suitable carrier, diluent, or excipient such as sterile water, physiological saline, glucose, and the like [para 173]. The sterile injectable preparation may also be a sterile injectable solution or suspension in a parenterally acceptable diluent or solvent. Suitable diluents include, for example, water, Ringer's solution and isotonic sodium chloride solution [para 174]. When in the form of solutions, suspensions and gels, in some embodiments, the formulations of the conjugates contain a major amount of water (preferably purified water) in addition to the active ingredient. Minor amounts of other ingredients such as pH adjusters, emulsifiers, dispersing agents, buffering agents, preservatives, wetting agents, jelling agents, colors, and the like can also be present [para 177]. The isotonicity of the compositions can be attained using inorganic or organic solutes. Sodium chloride is particularly preferred. Buffering agents can be employed, such as acetic acid and salts, citric acid and salts, boric acid and salts, and phosphoric acid and salts [para 178]. Pharmaceutically acceptable carriers for pulmonary delivery of the conjugates include carbohydrates such as sucrose [para 182]. Formulations for dispensing from a powder inhaler device typically comprise a finely divided dry powder containing the conjugate, optionally including a bulking agent, such as sucrose [para 185]. Formulations suitable for use with a nebulizer, either jet or ultrasonic, typically comprise the conjugate dissolved or suspended in water at a concentration of about 0.01 or less to 100 mg or more of conjugate per mL of solution [para 183]. The multivalent conjugate vaccine Salmonella enterica serovars are administered to a subject as a pharmaceutical composition, which may contain salts, buffers, adjuvants, or other substances which are desirable for improving the efficacy of the composition. Adjuvants are substances that can be used to specifically augment a specific immune response. Mineral adjuvants include mineral salts (for example, AlK(SO4)2, AlNa(SO4)2, AlNH4 (SO4) [para 170]. A pharmaceutically acceptable preservative can be employed to increase the shelf life of the compositions. Benzyl alcohol can be suitable, although a variety of preservatives including, for example, parabens, thimerosal, chlorobutanol, or benzalkonium chloride can also be employed. A suitable concentration of the preservative can be from 0.02% to 2% based on the total weight although there can be appreciable variation depending upon the agent selected [para 180]. S. Paratyphi A is a serovar that, like S. Typhi, is human host restricted and has a similar pathogenesis and causes an identical clinical syndrome (enteric fever) in humans as S. Typhi [para 249].
Therefore, it would have been prima facie obvious at the time of applicants’ invention to apply Levine et al’s pharmaceutical components such as sucrose, sodium chloride, and water into Ella and Konadu’s immunogenic composition comprising conjugated Salmonella enterica serovar paratyphi A and Salmonella enterica serovar in order to provide suitable formulations for improved efficacy of the composition. One of ordinary skill in the art would have a reasonable expectation of success by incorporating Levine’s ingredients to Ella and Konadu et al., conjugate composition because Levine teach the form of solutions where the formulations of the conjugates contain a major purified water in addition to the conjugate and minor amounts of other ingredients such as buffering agents and preservatives. Furthermore, no more than routine skill would have been required to incorporate the pharmaceutical ingredient of Levine et al., when Ella et al., already teach several of the same pharmaceutically acceptable components. Finally, it would have been prima facie obvious to combine the invention of Levine et al., Ella et al., and Konadu et al., to advantageously achieve an immunogenic composition against pathogenic S. enterica serovars Typhi and Paratyphi known to cause typhoid infections/fevers.
Additionally, KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007), discloses combining prior art elements according to known methods to yield predictable results, thus the combination is obvious unless its application is beyond that person's skill. KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007) also discloses that "The combination of familiar element according to known methods is likely to be obvious when it does no more than yield predictable results". It is well known to take an immunogenic composition, where there is no change in the respective function of the conjugates, thus the combination would have yielded a reasonable expectation of success along with predictable results to one of ordinary skill in the art at the time of the invention. Therefore, it would have been obvious to a person of ordinary skill in the art to combine prior art elements according to known methods that is ready for improvement to yield predictable results. The claimed invention is prima facie obvious in view of the teachings of the prior art, absent any convincing evidence to the contrary.
Response to Arguments
8. Applicant's arguments filed October 10, 2025 have been fully considered but they are not persuasive. The rejection of claims 130-136 and 154-155 under 35 U.S.C. 103 as being unpatentable over Ella et al., in view of Konadu et al. is maintained despite Applicants arguments. The rejection of claims 137-138 under 35 U.S.C. 103 as being unpatentable over Ella et al., in view of Konadu et al. as applied to claims 130-136, 144 and 154-155 above, and further in view of Levine et al., is maintained despite Applicants arguments.
Applicants argue that Konadu et al., provide preference to conjugation with Tetanus toxoid (TT) and does not provide any disclosure or teaching to the person skilled in the art to use the combination of OSP with diphtheria toxoid. However Konadu et al., clearly teach Salmonella enterica serovar paratyphi A O-specific polysaccharide (O-SP) bound to tetanus toxoid (TT). Konadu et al., teach S. enterica serovar Paratyphi A O-specific polysaccharide–TT conjugates were safe and elicited IgG antibodies with bactericidal activity in the serum of adults, teenagers, and small children. Therefore the argument is not persuasive.
In response to applicant’s argument that there is no teaching, suggestion, or motivation to combine the references, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). In this case, the Office set forth numerous reasons to combine the references. The Office pointed out that it would have been prima facie obvious to combine the invention of Ella et al., and Konadu et al., to advantageously achieve an immunogenic composition against pathogenic S. enterica serovars Typhi and Paratyphi known to cause typhoid infections/fevers. Additionally, it would have been prima facie obvious at the time of applicants’ invention to apply Konadu et al’s Salmonella enterica serovar paratyphi A O-specific polysaccharide (O-SP) conjugated to tetanus toxoid to Ella’s immunogenic composition comprising a Salmonella enterica serovar paratyphi A conjugate antigen and Salmonella enterica serovar typhi Vi polysaccharide conjugate antigen in order to treat typhoid fever. Moreover, the Office provides evidence no more than routine skill would have been required to incorporate the conjugate antigen when Ella et al., already teach a bivalent immunogenic composition comprising a conjugate vaccine containing Salmonella typhi Vi tetanus conjugate and Salmonella paratyphi A conjugate. Thus, one of ordinary skill in the art would have a reasonable expectation of success by incorporating Konadu et al., conjugate because it elicits a significant rise in the IgG anti-LPS titer upon injection.
Applicants argue that Levine does not teach or reasonably suggest a Salmonella enterica serovar paratyphi A OSP polysaccharide, much less one as part of a protein conjugation and in combination with a Salmonella enterica serovar typhi Vi polysaccharide conjugated to a tetanus toxoid. In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). In this case, Ella et al., clearly teach an immunogenic composition comprising a Salmonella enterica serovar paratyphi A conjugate antigen and Salmonella enterica serovar typhi Vi polysaccharide-tetanus toxoid (TT) conjugate antigen to treat typhoid fever. Konadu et al., clearly teach the conjugate of Salmonella enterica serovar paratyphi A with O-specific polysaccharide (OSP) and diphtheria toxoid (DT). Finally, Levine et al., teach multivalent Salmonella enterica serovar conjugate vaccines comprising conjugates including S. Typhi, S. Paratyphi A wherein the conjugates comprise a hapten antigen and a carrier antigen, wherein at least one of the hapten antigens or carrier antigens is characteristic of the Salmonella enterica serovar wherein the conjugate vaccines can be in admixed with sucrose, sodium chloride and/or water for injections. Therefore the combination of familiar element according to known methods is likely to be obvious when it does no more than yield predictable results. Therefore Applicants arguments are not persuasive and the rejection is maintained.
Pertinent Art
9. The prior art made of record and not relied upon is considered pertinent to applicant’s disclosure.
WO2009150543 Micoli teach two Vi conjugates have been prepared by carbodiimide-mediated synthesis, using adipic acid dihydrazide derivatized CRM197 a non-toxic variant of diphtheria toxin as carrier proteins.
WO2014124228 Malley et al., teach Vi polysaccharide of Salmonella typhi, and other pneumococcal polypeptide antigens as immunogenic compositions comprising such antigens for treating and preventing pneumococcal infection.
Konadu et al. (Infect Immun. 2000 Mar; 68(3): 1529–1534) prepared S. paratyphi A O-specific polysaccharide (O-SP) and coupled to tetanus toxoid.
Konadu et al., (WO1998026799 published June 1998. Priority to Dec 1996).
INFECTION AND IMMUNITY, July 1996, Vol. 64, No. 7, KONADU et al., "Synthesis, Characterization and Immunological Properties in Mice of Conjugates Composed of Detoxified Lipopolysaccharide of Salmonella Paratyphi A Bound to Tetanus Toxoid, with Emphasis on the Role of O Acetyls", pages 2709-2715.
Ali et al., Synthesis and immunogenicity evaluation of Salmonella enterica serovar Paratyphi A O-specific polysaccharide conjugated to diphtheria toxoid. (Hum Vaccin Immunother. 2014;10(6):1494-8. Epub 2014 Mar 6).
Ella et al., (WO2015029056 published March 2015; priority to Aug. 2014). Ella et al., teach a stable conjugate vaccine formulations for protection against Salmonella typhi, and methods of conjugation between Vi-polysaccharide of S.typhi to tetanus toxoid as the carrier protein, responsible for producing improved T-dependent immune response against Typhoid fever caused by Salmonella typhi.
U.S. Patent No. 9,011,871 (Myron M. et al.) teaches a multivalent Salmonella enterica serovar conjugate vaccines comprising conjugates of S. typhimurium, S. enteritidis, S. choleraesuis, S. typhi, S. paratyphi A and S. paratyphi B, wherein the conjugates comprise a hapten antigen and a carrier antigen, wherein at least one of the hapten antigens or carrier antigens is characteristic of the Salmonella enterica serovar.
Mitra M, Shah N, Ghosh A, Chatterjee S, Kaur I, Bhattacharya N, et al. Efficacy and safety of vi-tetanus toxoid conjugated typhoid vaccine (PedaTyph) in Indian children: School based cluster randomized study. Hum Vaccin Immunother (2016) 12(4):939–45.
Mohan VK, Varanasi V, Singh A, Pasetti MF, Levine MM, Venkatesan R, et al. Safety and immunogenicity of a vi polysaccharide-tetanus toxoid conjugate vaccine (Typbar-TCV) in healthy infants, children, and adults in typhoid endemic areas: a multicenter, 2-cohort, open-label, double-blind, randomized controlled phase 3 study. Clin Infect Dis (2015) 61(3):393–402.
Conclusion
10. No claims allowed.
11. Any inquiry concerning this communication or earlier communications from the examiner should be directed to JA-NA A HINES whose telephone number is (571)272-0859. The examiner can normally be reached Monday thru Thursday.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor Vanessa Ford, can be reached on 571-272-0857. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/JANA A HINES/Primary Examiner, Art Unit 1645